Efficacy of prehospital administration of tranexamic acid in trauma patients: A meta-analysis of the randomized controlled trials

Accepted Manuscript Efficacy of prehospital administration of tranexamic acid in trauma patients: A meta-analysis of the randomized controlled trials

Ayman El-Menyar, Brijesh Sathian, Mohammed Asim, Rifat Latifi, Hassan Al-Thani PII: DOI: Reference:

S0735-6757(18)30225-0 doi:10.1016/j.ajem.2018.03.033 YAJEM 57384

To appear in: Received date: Revised date: Accepted date:

16 January 2018 14 March 2018 14 March 2018

Please cite this article as: Ayman El-Menyar, Brijesh Sathian, Mohammed Asim, Rifat Latifi, Hassan Al-Thani , Efficacy of prehospital administration of tranexamic acid in trauma patients: A meta-analysis of the randomized controlled trials. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Yajem(2017), doi:10.1016/j.ajem.2018.03.033

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ACCEPTED MANUSCRIPT Efficacy Of Prehospital Administration Of Tranexamic Acid In Trauma Patients: A Meta-Analysis Of The Randomized Controlled Trials

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Ayman El-Menyar, MD 12, Brijesh Sathian , PhD2,Mohammed Asim, PhD2,Rifat Latifi,MD3, Hassan Al-Thani,MD4

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1Department of Surgery, Trauma Surgery, Clinical Research, Hamad General Hospital, Doha, Qatar 2Clinical Medicine, Weill Cornell Medical School, Doha, Qatar 3 Department of Surgery, Westchester Medical Center, Valhalla, NY, USA 4Department of Surgery, Trauma & Vascular Surgery, Hamad General Hospital, Doha, Qatar

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Running title: Prehospital tranexamic acid in trauma

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Correspondence: Ayman El-Menyar, MD Department of Surgery, Trauma Surgery, Clinical Research, Hamad General Hospital, P.O Box 3050, Doha, Qatar e-mail: [email protected]

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ayman El-Menyar: [email protected]

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Hassan Al-Thani: [email protected] Mohammed Asim: [email protected]

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Brijesh Sathian: [email protected] Rifat Latifi: [email protected]

Abstract Objective: Antifibrinolytic agent tranexamic acid (TXA) has a potential clinical benefit for in-hospital patients with severe bleeding but its effectiveness in pre-hospital settings remains unclear. We conducted a systematic review and meta-analysis to evaluate 1

ACCEPTED MANUSCRIPT whether pre-hospital administration of TXA compared to placebo improve patients’ outcomes? Methods: PubMed, MEDLINE, Cochrane Library, WHO International Clinical Trials Registry Platform, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus,

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and clinicaltrials.gov and Google scholar databases were searched for a retrospective,

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prospective and randomized (RCT) or quasi-RCT studies that assessed the effect of

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prehospital administration of TXA versus placebo on the outcomes of trauma patients with significant hemorrhage. The main outcomes of interest were 24 hours and 30-days

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mortality and in-hospital thromboembolic complications. Two authors independently

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abstracted the data using a data collection form. Results from different studies were pooled for the analysis, when appropriate.

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Results: Out of 92 references identified through the search, two analytical studies met the

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inclusion criteria. The effect of TXA on 24-hour mortality had a pooled odds ratio (OR) of 0.49 (95% CI 0.28–0.85), 30-days mortality OR of 0.86 (95% CI, 0.56–1.32), and

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thromboembolic events OR of 0.74 (95% CI, 0.27–2.07).

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Conclusion: Prehospital TXA appears to reduce early mortality in trauma patients. The pooled analysis also shows a trend towards lower 30-days mortality and reduced risk of

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thromboembolic events. Additional randomized controlled clinical trials are needed to determine the significance of these trends.

Keywords: Trauma, mortality, thromboembolic event, tranexamic Acid, pre-hospital

Introduction

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ACCEPTED MANUSCRIPT According to the World Health Organization, trauma accounted for 9% of the global mortality and is considered as a serious public health concern worldwide [1]. Scientific evidence reported traumatic bleeding to be the leading cause of early mortality in injured patients [2-5]. Around 25% of the trauma patients developed acute coagulopathy as

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complication and up to 40% of them died secondary to hemorrhagic shock [5-8]. Recent

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researches demonstrated that early treatment of acute coagulopathies and hemorrhagic

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shock considerably minimizes post traumatic deaths [6, 10]. Suspected non-compressible bleeding that leads to hemodynamic instability should be managed through fluid

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resuscitation, permissive hypotension, administration of tranexamic acid, and rapid

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transport to the nearest suitable center [11]. Tranexamic acid (TXA) is cost effective antifibrinolytic agent and its early (within 3 h post injury) in-hospital administration in

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patients with trauma-induced hemorrhagic shock showed significant reduction in

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mortality and thromboembolic events [12-14]. By effectively controlling bleeding at early stage post trauma, TXA has the potential to prevent the subsequent hypoxia and

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acidosis that complicate severe bleeding. Based on two large studies, it appears that TXA

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shows time-dependent effect and potential benefit in the treatment of hemorrhagic shock in the civilian and military populations [12,15]. However, these earlier studies primarily

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focused on the in-hospital use of TXA in trauma patients. Currently, European guidelines for management of major bleeding and coagulopathy following trauma, recommended early administration of TXA to prevent bleeding [16]. To date, the evidence of prehospital TXA use in trauma patient is debatable due to lacking of published randomized control studies. Herein, we conducted a systematic

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ACCEPTED MANUSCRIPT review and meta-analysis as the first update on the current evidence regarding the efficacy of the prehospital use of TXA in trauma patients. Objective The objective of this study is pooling of effects of prehospital TXA administration on the

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complications during the hospital course in civilian population.

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mortality at 24 hours and 30 days, and to evaluate the risk of developing thromboembolic

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Methods

This systematic review was conducted and reported according to the Preferred

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Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. The

(PROSPERO n. CRD42017077517).

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Literature searches

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study was registered at the International prospective register of systematic reviews

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A systematic review was carried out using PubMed, MEDLINE, Cochrane Library, WHO International Clinical Trials Registry Platform, Cochrane Central Register of

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Controlled Trials (CENTRAL), Scopus, and clinicaltrials.gov and Google scholar

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electronic databases. We used the keywords “Tranexamic Acid”; “prehospital setting”; “point of injury”; “trauma” [in Title/Abstract]. The medical subject headings (MeSH)

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terms used were prehospital [All Fields] AND ("tranexamic acid"[MeSH Terms] OR ("tranexamic"[All Fields] AND "acid"[All Fields]) OR "tranexamic acid"[All Fields]) AND ("injuries"[Subheading] OR "injuries"[All Fields] OR "trauma"[All Fields] OR "wounds and injuries"[MeSH Terms] OR ("wounds"[All Fields] AND "injuries"[All Fields]) OR "wounds and injuries"[All Fields]). Additional searches were conducted using reference lists of studies and review articles for a selection of relevant articles.

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Inclusion/exclusion criteria The inclusion criteria were (1) original studies, (2) English language, (3) published in the period from 01 January 2000 through 31st August 2017 (4) assessed Tranexamic Acid” or

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“prehospital” and “traumatic injury” (5) patient population (6) patients of any age,

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gender, and ethnicity. Articles other than original studies such as case reports, reviews,

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letters to the editor and commentaries were excluded. Literatures that did not include

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comparisons or outcomes were also excluded.

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The consensus on inclusion/exclusion criteria was reached based on the fact that whether the study provides information about the efficacy of TXA [mortality at 24 hours and 30

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days, and thromboembolic complications] in prehospital setup in patients’ sustained

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traumatic injury. Therefore, even studies with smaller sample sizes were also included in the initial evaluation.

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Definitions:

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Participants: Traumatic injury patients presenting to the ED requiring blood transfusions.

trauma.

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Intervention: pre hospital tranexamic acid administration at any dose and route after

Control: Placebo administration. Outcomes: 24 hours mortality, 30 days mortality, and thromboembolic events. We considered any plausible definitions used by original articles Thromboembolic complications: Symptomatic thromboembolic complications are diagnosed when patients

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ACCEPTED MANUSCRIPT showed significant clinical signs or symptoms /radiological evidence of deep venous thrombosis or pulmonary embolism. Data extraction The titles of the research articles obtained from the initial database searches were

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screened and relevant papers were selected. Then the abstracts and full texts were

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reviewed according to the inclusion criteria for final selection. The titles, abstracts, and

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full-text articles were reviewed independently by two researchers (AE & BS). Agreement between the authors on the quality of the articles ranged between 90 to 100%. All the

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disagreements were resolved by consensus among the authors. Extracted data included

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authors, the origin of studies, source population, study settings and duration, inclusion/exclusion criteria, data sources and measurement, sample size, thromboembolic

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complications and mortality at 24 hours and 30-days.

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Methodological quality

We used “Grading quality of evidence and strength of recommendations” (GRADE

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criteria) to assess the quality of the included studies and rate the level of evidence. The

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methodological quality of the selected studies was assessed based on certainty assessment [Study design, Risk of bias, Inconsistency, Indirectness, Imprecision, and Other

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considerations] by Cochrane Grade pro software. We have evaluated the quality of the proposed outcomes i.e. thromboembolic complications and mortality at 24 hours and 30days. Data Analysis and Synthesis Odds ratios (OR) were calculated for categorical variables.

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ACCEPTED MANUSCRIPT The decision to select either fixed effect or random effects model depends on results of statistical tests for heterogeneity. Data heterogeneity was assessed using the Cochrane Q homogeneity test with significance set at p < 0.10. If the studies were statistically homogeneous, fixed effect model was selected. A random effects model was used when

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studies were statistically heterogeneous. The I2 test is the ratio of true heterogeneity to the

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total variation in observed effects. A rough guide to interpretation of I2 test is 0 to 25 %:

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might not be important; 25 to 50 %: may represent moderate heterogeneity; 50 to 75 %: may represent substantial heterogeneity; and more than 75%: considerable heterogeneity.

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Pooled estimates of mortality were calculated using a Microsoft Excel add-in, MetaXL v.

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5.3 (EpiGear International Pty Ltd, Sunrise Beach, Queensland, Australia). GRADEpro

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GDT was used for studies grading.

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Results

The search produced a total of 92 articles; 75 article were either non relevant to the topic,

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duplicates or review articles which were excluded initially. The relevant titles and/or

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abstracts and full text of the 17 articles underwent detailed evaluation; of which 7 articles were further eliminated which were mainly based on protocol development and narrative

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reviews and the remaining 10 articles studies [17-24] were reviewed further. Among them 8 studies [19-24] were excluded as per the criteria for meta-analysis [mortality at 24 hours and 30 days, and thromboembolic complications] and availability of only abstracts. Among the 8 excluded studies 7 [8, 19-21, 22, 24] did not have controls and did not assess the outcome measures. One study had controls but did not have outcome measures [23]. Finally, two original studies met all the review criteria and were considered for the

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ACCEPTED MANUSCRIPT final meta-analysis (Figure 1, Table 1). Both the studies lasted for 3 years. The total number of patients pooled was 769, of which 386 were in TXA group and 383 in control group. The first study [18] was a retrospective analysis, in which a cohort of patients who received prehospital TXA was compared to a propensity score-based matched control.

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TXA was provided by 20 of the 35 air rescue helicopters during the 3-year study period.

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Early mortality was significantly lower in the TXA cohort (5.8% vs 12.4%). However,

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the overall in-hospital mortality was comparable among the two groups (p=0.72). The mean time to death was significantly longer in TXA group (8.8 vs 3.6 days). No

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significant differences were observed between the intervention and control groups in

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terms of the thromboembolic events.

In the second study, 253 trauma patients were prospectively recruited [17]. Although, it

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was not statistically significant, the prehospital intervention group trended toward a lower

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24-h (p=0.25), 48-h (p=0.76), and 28-day mortality rates (p=0.23). Furthermore, a reduction in the total number of blood products was observed following the

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administration of TXA (p=0.01).

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Table 2 shows details of the quality assessment based on GRADE criteria of the two selected studies. Both studies were of moderate quality. Table 3 & Supplementary file

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demonstrate the quality assessment of the included studies which shows the moderate level of evidence based on the GRADE criteria.

Outcome measures Effect of TXA on 24-hour mortality

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ACCEPTED MANUSCRIPT Only 2 prehospital TXA studies compared the 24-hour mortality in the TXA group with a control group. Total of 61 patients died within 24 hours of injury [20 in TXA group and 41 in Placebo group] and a post hoc statistical power of 93%. Therefore, we considered these studies for the meta-analysis (Figure 2). The pooled result manifested a statistically

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significant reduction in 24-hour mortality in the intervention group compared to the

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control group (OR 0.49; 95% CI, 0.27 to 0.84).

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Effect of TXA on 30-days mortality

We pooled the results from these two studies in Figure 3. Total of 99 patients died within

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30 days of injury [44 in TXA group and 55 in Placebo group] and a post hoc statistical

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power of 23.6%. The pooled results indicated a trend of reduction for 30-days mortality in the intervention group with respect to the control group but it did not reach statistical

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significance (OR 0.86; 95% CI, 0.559 to 1.32).

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Effect of TXA on thromboembolic events

Total of 18 patients developed thromboembolic events during hospital stay [6 in TXA

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group and 12 in Placebo group] and a post hoc statistical power of 29.7%. The pooled

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result showed a non-significant trend of reduction in thromboembolic events in the intervention group as compared to the controls (OR 0.74; 95% CI, 0.267 to 2.066)

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(Figure 4). Although the latter 2 outcomes were statistically not significant because of less statistical power, both might still have clinical implications.

DISCUSSION

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ACCEPTED MANUSCRIPT Although, there is no published randomized clinical trial (RCT) yet, at least 10 published studies have addressed the beneficial effect of prehospital TXA use for the treatment of significant bleeding in trauma patients [8,16-24]. Up to the best of our knowledge, this is the first attempt to conduct a meta-analysis in this regard. Literature searching and data

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analysis for the present meta-analysis resulted in two moderate-quality observational

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studies described the hypothesis that prehospital administration of TXA in civilian

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trauma patients would reduce the risk of mortality and thromboembolic complications compared to placebo [17, 18]. The first study was under-powered prospective study with

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wide confidence intervals, whereas the second study was retrospective and appropriately

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powered to measure the study outcomes [17,18].

Our findings suggest that prehospital TXA administration could effectively reduce early

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mortality with a trend of improved survival at 30-day post-traumatic injury. Although, the

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pooled results for the 30-day mortality did not get enough power to reach statistical significance, the results still have clinical implications. Furthermore, prehospital TXA

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did not increase the thromboembolic events in those who received TXA, compared to

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controls.

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TXA in Emergency Department (ED): Prior systematic reviews have shown that TXA is an effective peri-operative drug that minimizes the blood loss during elective surgery in trauma and non-trauma patients in the hospital settings (25-28). The effect of TXA was shown to be time-dependent and better outcomes were observed for the hospital TXA administration within 3 h post injury in polytrauma patients [8,10,16-19,21,22].

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ACCEPTED MANUSCRIPT There are 2 meta-analyses assessed TXA use in the ED [29,30]. Zehtabchi et al conducted a meta-analysis of only two studies that evaluated the in-hospital use of TXA in patients with traumatic brain injury [29]. These investigators showed the favorable effect of TXA on the overall mortality with a pooled relative risk of 0.64 which did not

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reach statistical significance. However, the risk of thromboembolic event was not

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accounted in the study outcome. The other meta-analysis quantified the efficacy of TXA

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use in reducing the risk of bleeding and thromboembolic events in patients undergoing orthopedic trauma surgery [30]. There was no significant difference in the risk of

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thromboembolic events (OR 0.97; p = 0.68) between the TXA and control groups .

TXA in CRASH-2 and its sub-analysis: In the CRASH-2 study, the 28 days mortality

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rate was significantly reduced with TXA use in the ED (14·5% in TXA group vs 16·0%

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in placebo group) with a relative risk of 0·91(p=0·003) [12]. In a sub-analysis of this study, Roberts et al showed that , after giving TXA in the ED, the risk ratio of mortality

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was 0·68 (TXA given within the first h) and 0·79 (TXA given within the second or third

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h) [14]. Therefore, it is worth to further investigate how early the administration of TXA

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in trauma patient could be.

Pre-hospital TXA in the contemporary literature: A recent narrative review by Pinto et al [31] evaluated two articles which studied prehospital TXA use in a pooled sample of 53 trauma patients [19,21]. The authors suggested that, based on the available literature, it could be safe to use TXA in the prehospital settings. The review identified single observational study which aimed to assess the occurrence of thromboembolic events

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ACCEPTED MANUSCRIPT related to TXA use in trauma patients. Similar to our findings, no significant difference was observed in that study for thromboembolic events in patients receiving TXA versus controls [32]. Thus, the accumulated evidence to date points to the safety of treatment with TXA; however, there is still need for further RCTs designed to evaluate the safety

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and efficacy of prehospital TXA use in trauma patients in terms of complications and

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mortality. We do believe that inclusion of findings from the ongoing clinical trials for

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prehospital TXA administration can yield sufficient power to get a statistical significance

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in the near future [29,30,33].

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Pre-hospital TXA in Meta-analysis and Clinical Trials: There is no prior metaanalysis addressed the TXA use in the prehospital settings so far, however, there are 3

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ongoing clinical trials to investigate the safety and efficacy of prehospital TXA use in

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trauma patients [33,34,35]. Recently, few investigators have evaluated the use of prehospital TXA in trauma patients’ in civilian and military settings and had shown the

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feasibility of its use in the field [11,20,23]. However, there is a lack of high level of

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evidence based on clinical trials with sufficient statistical power to determine the safety

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and efficacy of prehospital TXA use.

Recommendations For The Early Use Of TXA: Recently, the Department of Defense Committee on Tactil Combat Casualty Care (CoTCCC) supported the TXA use within the first 3 h post-injury at the prehospital settings if the there is a need for significant blood transfusion ( shock, ≥1 amputations, penetrating abdominal injury or severe bleeding) [36] . Furthermore, there is a recommendation that the use of TXA under these

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ACCEPTED MANUSCRIPT settings should be preceded by the thromboelastography (TEG) evidence of hyperfibrinolysis (i.e., percent lysis at 30 minutes >3%) according to the Denver experience [37]. However, TEG may not be feasible in the EMS settings and in most of ED and if presents, a trained staff should be there to avoid the delay of treatment. Also,

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occult hyperfibrinolysis in trauma may not be easily detected by viscoelastic studies

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including TEG [38]. A recent prospective, multicenter study assessed the coagulation

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profiles in 70 trauma patients receiving TXA on-scene vs 38 historic control patients who did not receive TXA.

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The investigators used ROTEM for clotting assay at the scene and ED and found that the

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production of fibrinogen fragments was significantly lower in the TXA group. The authors concluded that early prehospital administration of TXA leads to clot stabilization

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and a reduction of fibrinolytic activity, however, the study had a limitation of having a

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small sample size [39]. Few trauma centers have advocated or recommended the integration of TXA protocol in their prehospital phase by EMS in an attempt to provide

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an adjunct to early hemorrhage control [Table 4] [40,41].

As the contemporary literature is in favor of giving TXA as early as possible as the

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mortality and thromboembolic events are fewer compared to the controls, our findings would have implications for the clinical care of trauma patients particularly in the prehospital settings.

LIMITATIONS: The searches for this review were in most of the citation databases and reference lists from included studies. We have accessed the paid articles as well.

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ACCEPTED MANUSCRIPT Some limitations exist in the current study meta-analysis of the evidence. Our study included only the published studies and the information of ongoing clinical trials. We could not find out the gray literature that is not published and so we admit the potential publication bias. We had only two studies and one of them did not have sufficient power

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and reported 28-day mortality. The total number of patients that received TXA was under

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400. One study was prospective, but the other one was retrospective. Neither was

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randomized trial. Comparison groups were propensity matched or historical. Also, the information about transfusion volumes, the exact timing of prehospital TXA

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administration and dosages were missing, the cause of death was not documented,

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therefore deaths occurred due to hemorrhage or TBI are unknown, cannot determine whether TXA was associated with reduced mortality due to hemorrhage. While this fact

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limits the generalizability of the findings, the quality of the included studies and absence

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of significant heterogeneity validates the present analysis. We included only civilian injuries in the analysis. The inclusion of only 2 studies in this meta-analysis could be one

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of the limitations, however, we have done a post hoc power calculation for 24 h mortality

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comparison, there were 41 mortality out of 383 in control group and 20 out of 386 in intervention group which showed a power of 92.62 at 5% significance level.

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Furthermore, Valentine et al, in their review, tried to answer about how many studies do we need to do a meta-analysis?’’ and they showed that, given the need for a conclusion, the answer was ‘‘two studies,’’ because all other synthesis techniques are less transparent and/or are less likely to be valid [42]. In conclusion, prehospital TXA significantly reduces early mortality in trauma patients. The pooled analysis also indicated lower 30-days mortality and reduced risk of

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ACCEPTED MANUSCRIPT thromboembolic events with the prehospital TXA use in trauma patients. Although the latter two outcomes were statistically not significant, both might still have clinical implications. Furthermore, high-quality randomized controlled trials are needed to support the routine use of prehospital TXA in major trauma patients. Although there are

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no enough eligible studies yet, the results of our attempt can be taken cautiously in

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consideration until proven otherwise. This information will substantiate the proposed

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beneficial effect of TXA administration for prehospital protocol development.

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Acknowledgment: we thank all the research office team at the trauma and vascular

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surgery units at HMC.

Consent to participate: N/A

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Consent for publication: N/A.

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Ethical approval: N/A

Availability of data and material: N/A

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Competing interests: The authors have no conflict of interest, no financial issues to

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disclose and no funding was received for this study. Funding: This research did not receive any specific grant from any funding agency in the

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public, commercial or not-for-profit sector. Author’s contribution: All authors contributed substantially in the design of the study interpretation of the data, writing the manuscript and approving the submission

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2015 ;34(1):37-9.

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23. Schauer SG, April MD, Naylor JF, Wiese J, Ryan KL, Fisher AD, Cunningham CW, Mitchell N, Antonacci MA. Prehospital Administration of Tranexamic Acid by Ground

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Forces in Afghanistan: The Prehospital Trauma Registry Experience. J Spec Oper Med.

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2017;17(3):55-58.

24. Kunze-Szikszay N, Krack LA, Wildenauer P, Wand S, Heyne T, Walliser K, Spering

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C, Bauer M, Quintel M, Roessler M. The pre-hospital administration of tranexamic acid

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to patients with multiple injuries and its effects on rotational thrombelastometry: a prospective observational study in pre-hospital emergency medicine. Scand J Trauma

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Resusc Emerg Med. 2016 ;24(1):122. 25. Yeguiayan J, Rosencher N, Vivien B. Early administration of tranexamic acid in trauma patients. Lancet 2011; 378(9,785): 27–8. 26. Kakar PN, Gupta N, Govil P, Shah V. Efficacy and safety of tranexamic acid in control of bleeding following TKR: a randomized control trial. Indian J Anaesth 2009;53:667-71.

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ACCEPTED MANUSCRIPT 27. Movafegh A, Eslamian L, Dorabadi A. Effect of intravenous tranexamic acid administration on blood loss during and after cesarean delivery. Int J Gynaecol Obstet 2011;115:224-6. 28. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical

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bleeding: systematic review and cumulative meta-analysis. BMJ. 2012 May

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29. Zehtabchi S, Abdel Baki SG, Falzon L, Nishijima DK. Tranexamic acid for traumatic brain injury: a systematic review and meta-analysis. Am J Emerg Med. 2014

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Dec;32(12):1503-9. doi: 10.1016/j.ajem.2014.09.023.

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30. Gausden EB, Qudsi R, Boone MD, O'Gara, B, Ruzbarsky JJ, Lorich DG. Tranexamic Acid in Orthopaedic Trauma Surgery: A Meta-Analysis.J Orthop Trauma. 2017; 31(10):

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31. Pinto MA, da Silva JG, Chedid AD , Chedid MF. Use of tranexamic acid in trauma patients: an analysis of cost-effectiveness for use in Brazil. ABCD Arq Bras Cir Dig

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2016;29(4):282-286. DOI: /10.1590/0102-6720201600040017

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32. Van Haren RM, Valle E, Busko AM, Guarch GA, Jouria JA, Namias N, Livingstone AS, Proctor KG. Safety and efficacy of tranexamic acid in trauma patients at high risk for

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venous thromboembolism. 2013. J Am Coll Surg. 217. S49. 10.1016/j.jamcollsurg.2013.07.099. 33. Gruen R. Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage (The PATCH Study) (PATCH). ClinicalTrials.gov. Identifier:NCT02187120. [Cited on 18-09-2017]. Available at: https://clinicaltrials.gov/ct2/show/NCT02187120?term=NCT02187120&rank=1

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ACCEPTED MANUSCRIPT 34. May S. Prehospital Tranexamic Acid Use for Traumatic Brain Injury (TXA). ClinicalTrials.gov Identifier: NCT01990768. [Cited on 18-09-2017]. Available at: https://clinicaltrials.gov/ct2/show/NCT01990768 35. Sperry J. Study of Tranexamic Acid During Air Medical Prehospital Transport Trial

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(STAAMP Trial) (STAAMP). ClinicalTrials.gov Identifier: NCT02086500. [Cited on 18-

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09-2017]. Available at: https://clinicaltrials.gov/ct2/show/NCT02086500

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36. Huebner BR, Dorlac WC, Cribari C.Tranexamic Acid Use in Prehospital Uncontrolled Hemorrhage.Wilderness Environ Med. 2017 Jun;28(2S):S50-S60

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37. Chapman MP1, Moore EE, Ramos CR, Ghasabyan A, Harr JN, Chin TL, Stringham

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JR, Sauaia A, Silliman CC, Banerjee A. Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy. J Trauma Acute Care Surg. 2013;75(6):961-7.

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38. Napolitano LM1, Cohen MJ, Cotton BA, Schreiber MA, Moore EE.Tranexamic acid

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in trauma: how should we use it? J Trauma Acute Care Surg. 2013 Jun;74(6):1575-86. 39. Stein P, Studt JD, Albrecht R, Müller S, von Ow D, Fischer S, Seifert B,

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Mariotti S, Spahn DR, Theusinger OM. The Impact of Prehospital Tranexamic Acid on

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Blood Coagulation in Trauma Patients. Anesth Analg. 2017 Dec 11. doi: 10.1213/ANE.0000000000002708

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40. Fischer PE, Bulger EM, Perina DG, Delbridge TR, Gestring ML, Fallat ME, Shatz DV, Doucet J, Levy M, Stuke L, Zietlow SP, Goodloe JM, VanderKolk WE, Fox AD, Sanddal ND. Guidance Document for the Prehospital Use of Tranexamic Acid in Injured Patients. Prehosp Emerg Care. 2016;20(5):557-9. 41. Thurston B, Chowdhury S, Edu S, Nicol AJ, Navsaria PH. Time since injury is the major factor in preventing tranexamic acid use in the trauma setting: An observational

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ACCEPTED MANUSCRIPT cohort study from a major trauma centre in a middle-income country. S Afr J Surg. 2015 Oct 8;53(1):13-8. 42. Valentine JC, Pigott TD, Rothstein HR : How Many Studies Do You Need? A Primer on Statistical Power for Meta-Analysis. Journal of Educational and Behavioral Statistics.

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Figure legends

Figure 1: Flow diagram of study selection process for systematic review.

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Figure 2: Forest plot representing the effect of tranexamic acid on 24-hour mortality

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Figure 3: Forest plot representing the effect of tranexamic acid on 30 days mortality Figure 4: Forest plot representing the effect of tranexamic acid on thromboembolic

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ACCEPTED MANUSCRIPT Table 1: summary and assessment of the eligible studies for the current meta-analysis Conclusion

Limitations

- Early mortality was significantly lower in the TXA group. - Complications and overall hospital mortality was similar in both groups.

TXA was associated with prolonged time to death and significantly improved early survival

- Initial implementation of TXA administration between the prehospital and hospital groups did not occur simultaneously. - The delayed onset of TXA administration in the prehospital group was due to the need for approval by local and state EMS regulatory authorities, as well as personnel training for administration in the prehospital setting. - This study was limited by design. The prospective cohort design in comparison to a randomized control design did not allow us to administer TXA in a blinded fashion.

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Findings

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128 TXA administrated and 125 control matched based upon ISS, hemodynamic profiles, and mechanism of injury

Inclusion criteria Criteria for the prehospital and hospital use of TXA : •Blunt or penetrating trauma with signs and symptoms of hemorrhagic shock •SBP <90 mmHg at scene of injury, during air and/or ground medical transport, or upon arrival to designated trauma centers •Any sustained blunt or penetrating injury <3h •Patients high risk for significant hemorrhage (Estimated blood loss of 500 ml at scene accompanied with a heart rate >120; uncontrolled bleeding by direct pressure or tourniquet, Major amputation of any extremity above the wrists and above the ankles Patients were treated with TXA at the discretion of the emergency physician.

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Sample size

Retrospective (Prehospital) Civilian January 2012 and December 2014

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Wafaisade et al [18]

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Neeki et al [17]

Study design & Duration Prospective (Prehospital) Civilian 2014-2016

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Study

258 TXA administrated and 258 propensity matched controls

- Early mortality was significantly lower in the TXA group. - Complications and overall hospital mortality was similar in both groups.

TXA was associated with prolonged time to death and significantly improved early survival

- Laboratory parameters (e.g., D-dimers, thromboelastometry, interleukin-6) not available. - exact timing of prehospital TXA administration and dosages (TXA or fibrinogen) not documented.

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Table 2: Quality assessment of the included studies in the meta-analysis Neeki MM et al (Germany) 2017 [17]

Wafaisade et al (Germany) 2016 [18]

Study Design

Non-RCT.

Non-RCT.

Prospective study

Retrospective study

(Prehospital)

(Prehospital)

Low or unclear risk of bias. Plausible bias unlikely to seriously alter the results.

Low or unclear risk of bias. Plausible bias unlikely to seriously alter the results.

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This study has no serious risk of bias, which does not downgrade the quality.

No

No

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This study has no serious risk of bias, which does not downgrade the quality.

The study population was Civilian, Intervention was TXA vs No TXA, and Outcome assessment was consistent in terms of mortality (24 hour and 30 days) and thromboembolic events.

The study population was Civilian, Intervention was TXA vs No TXA, and Outcome assessment was consistent in terms of mortality (24 hour and 30 days) and thromboembolic events.

There is no indirectness as all adult trauma patients with risk of bleeding were included, intervention was same dose of TXA, and comparator group was similar, outcome measure was appropriate to assess the effect of intervention.

There is no indirectness as all adult trauma patients with risk of bleeding were included, intervention was same dose of TXA, and comparator group was similar, outcome measure was appropriate to assess the effect of intervention.

There is possibility of imprecision because of wide confidence interval.

There is no possibility of imprecision. It does not appear to be an issue.

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24 hours mortality [OR 0.47(0.25, 0.89)]

24 hours mortality [OR 0.54(0.18, 1.66)]

30 days mortality [OR 0.86(0.53, 1.38)]

30 days mortality [OR 0.87(0.32, 2.32)]

Thromboembolic events [OR 0.67(0.20, 2.22)]

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Thromboembolic events [OR 0.98 (0.14, 7.04)] There is no publication Bias, Large effect, dose response gradient. But anticipated plausible confounding factor might reduce demonstrated effect because it is a prospective non RCT. In addition, there may be publication bias because of less sample size.

There is no publication Bias, Large effect, dose response gradient. But anticipated plausible confounding factor might reduce demonstrated effect because it is a retrospective non RCT.

Quality of evidence

Moderate

Moderate

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ACCEPTED MANUSCRIPT Table 3: Quality assessment of the eligible studies: Tranexamic Acid vs. No Tranexamic Acid be used for Pre hospital Trauma Patients Patient or population: Trauma Patients Setting: Prehospital Intervention: Tranexamic Acid

37 per 1,000 (21 to 62)

High

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Low

104 per 1,000

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Mortality assessed with Time: 30 days

Comments

386 cases 383 controls (2 observatio nal studies)

⨁⨁⨁◯ MODERA TE

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OR 0.86 (0.56 to 1.32)

386 cases 383 controls (2 observatio nal studies)

⨁⨁⨁◯ MODERA TE

IMPORTA NT

OR

386 cases

⨁⨁⨁◯

IMPORTA

OR 0.49 (0.28 to 0.85)

Thromboemb

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High 163 per 1,000

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65 per 1,000 (38 to 107)

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№ of participant s (studies)

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Relati ve effect (95% CI)

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Anticipated absolute effects* (95% CI) Risk with Risk with No Tranexa Tranexa mic Acid mic Acid Low

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Comparison: No Tranexamic Acid

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12 per 1,000 (4 to 33)

High 39 per 1,000

0.74 (0.27 to 2.07)

29 per 1,000 (11 to 77)

383 controls (2 observatio nal studies)

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*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio

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GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

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Table 4 : Q&A for prehospital administration of tranexamic acid Question & Problem Comment &Recommendation Bleeding trauma patients did not present TXA may be more effective on a population basis within the timeframe allowed for safe and if incorporated into prehospital protocols effective use of TXA in most of cases. The keys to survival remain the prompt - Prehospital TXA use should never replace hemorrhage control and rapid transport to a field bleeding control techniques, rapid trauma center in the bleeding patient. transport to a trauma center, or the administration of blood or plasma. - TXA administration should never delay transport TXA use includes a bolus dose followed by Prior to the implementation of field TXA, the an infusion over 8 h. EMS agency and the receiving trauma center should jointly develop protocols to ensure eligible patients receive the appropriate bolus dose in the field and infusion dose at the hospital -Hand-over confusion and dose missing or - A clear hand-off care report given by duplication may occur EMS providers is essential step, -Repeat bolus doses of TXA should be - Endorsement should states that TXA avoided bolus has been given during transport to avoid repeat bolus doses and to ensure that infusion is initiated in a timely fashion. - Prehospital TXA administration should be clearly communicated with the next receiving provider. Simple adjuncts, such as stickers or wristbands applied to patients, may be used to aid in the information transfer Limited evidence suggests that more venous - indications should be based on evidence thromboembolic consistent with non-compressible hemorrhage in events may occur when TXA is given to terms of penetrating thorax or abdominal trauma patients not requiring massive transfusion or unstable pelvis fractures along with heart rate >120 bpm and systolic blood pressure <90 mmHg - vital sign may be adjusted for geriatric population Compressible bleeding should be managed Prehospital TXA should be administered only to with pressure dressings, hemostatic agents, patients with non-compressible bleeding. wound packing, or tourniquets. Definitive surgical control at a trauma center Patients receiving prehospital TXA should be is need. transported to a Level I or II trauma center if available. If geographic or other factors preclude direct the first receiving hospital should be capable of trauma center transport continuing the TXA infusion and implementing hemorrhage-control procedures Administration should be reviewed and - Prehospital TXA use should be monitored protocols constantly refined to avoid closely in a prehospital and/or trauma unnecessary or incomplete doses, registry. inappropriate patient selection, or lack of - TXA dosing, timing, blood transfusion infusion following the initial bolus. requirements, and any adverse events 29

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-Children were excluded from the CRASH2 Trial. -The risk of TXA is seizures in pediatric population. Information adopted from ref 40,41

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-In the case of trauma patients known to be on chronic anticoagulants -The effect of administering TXA in conjunction with other medications used to reverse anticoagulants may lead to more thrombotic complications

should be included in the registry Fibrinolysis as measured by percent clot lysis at 30 minutes after reaching maximum clot strength should be collected in the trauma registry Medical control should be consulted prior to TXA administration if specific protocols for this situation have not been developed.

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Figure 1

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Figure 4